Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression
David J. Donnelly,R. Adam Smith,Paul E. Morin,Dasa Lipovsek,Jochem Gokemeijer,Daniel Cohen,Virginie Lafont,Tritin Tran,Erin L. Cole,Martin C. Wright,Joonyoung Kim,Adrienne Pena,Daniel W. Kukral,Douglas D. Dischino,Patrick L Chow,Jinping Gan,Olufemi Adelakun,Xi-Tao Wang,Kai Cao,David Leung,Samuel J. Bonacorsi,Wendy Hayes +21 more
TLDR
The feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies is demonstrated by 18F-BMS-986192, which bound to tumor tissues as a function of PD- L1 expression determined by immunohistochemistry.Abstract:
The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after 18F-fluorine labeling. Methods: An anti-PD-L1 adnectin was labeled with 18F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results:18F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(-)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti-PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1-specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1-rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E-01 mSv/MBq. Conclusion:18F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18F-BMS-986192 are under way to measure PD-L1 expression in human tumors.read more
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Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer
Anna-Larissa N. Niemeijer,David Leung,Marc C. Huisman,Idris Bahce,Otto S. Hoekstra,G.A.M.S. (Guus) van Dongen,Ronald Boellaard,Shuyan Du,Wendy Hayes,Ralph Adam Smith,Albert D. Windhorst,N.H. Hendrikse,Alex J. Poot,Danielle J. Vugts,Erik Thunnissen,Paul E. Morin,Dasa Lipovsek,David J. Donnelly,Samuel J. Bonacorsi,Linda M. Velasquez,T.D. de Gruijl,Egbert F. Smit,A.J. de Langen,A.J. de Langen +23 more
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ImmunoPET: Concept, Design, and Applications
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PET Imaging of Tumor PD-L1 Expression with a Highly Specific Nonblocking Single-Domain Antibody.
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TL;DR: Current biomedical imaging approaches used to monitor responses to treatment in patients receiving novel targeted therapies are described, including a summary of the most promising future approaches and how these might improve clinical practice.
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Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology.
Ahmet Krasniqi,Matthias D'Huyvetter,Nick Devoogdt,Fredrik Y. Frejd,Jens Nørkær Sørensen,Jens Nørkær Sørensen,Anna Orlova,Marleen Keyaerts,Vladimir Tolmachev +8 more
TL;DR: This mini review focuses on small proteins for radionuclide-based imaging that would allow same-day imaging, with the emphasis on clinical applications and promising preclinical developments within the field of oncology.
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TL;DR: Evaluated data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment, as well as across multiple cancer types.
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